The physical interaction of particulates with resident mononuclear phagocytes is a consistent feature in certain forms of crystal-induced inflammation. In this study, we observed that monosodium urate crystals stimulated the rapid release of neutrophil chemotactic activity from monocytes, and that this activity steadily increased over 24 hours. Because the release of monocyte-derived neutrophil chemotactic activity was markedly diminished by pretreatment of the monocytes with cycloheximide, and was completely removed from conditioned media by adsorption to heparin-agarose, we addressed the possibility that monocyte-derived neutrophil chemotactic factor/interleukin-8 (IL-8), a heparin-binding neutrophil-activating polypeptide, might modulate these activities. Urate crystal-induced IL-8 secretion from monocytes was verified by radioimmuno-assay. In addition, an IL-8–specific antibody markedly inhibited the neutrophil-activating capacity of the conditioned media from monocytes activated by urate crystals, as well as by inflammatory silica crystals. Last, IL-8 was significantly increased in gouty synovial fluids (range 3.0–16.8 ng/ml, mean 8.4 ng/ml, n = 6) relative to osteoarthritic synovial fluids (range 1.1–1.7 ng/ml, mean 1.5 ng/ml, n = 6) (P = 0.006). We conclude that microcrystal-induced secretion of IL-8 by mononuclear phagocytes may mediate a number of forms of crystal-induced inflammation.